This invention relates to the field of controlled delivery of peptides or proteins and to compositions useful for the controlled delivery of peptides or proteins.
Polymeric matrices, typically in the form of microspheres, rods, sheets or pellets, have been employed for the sustained or controlled release of drug products. A variety of techniques are known by which active agents can be incorporated into polymer matrices. Examples are solvent evaporation, spray drying, emulsification, or by simple physical mixing of particles of discrete size or shape. None of these approaches can easily be adapted to the incorporation of peptide or protein drugs into polymers due to the delicate nature of peptides and proteins. Peptides and proteins are susceptible to denaturation by solvents, by emulsification or by heat. In order to avoid the instability problem, U.S. Pat. No. 5,019,400 describes a very low temperature casting process for incorporating proteins into controlled release polymer matrices. This technique has several drawbacks, inasmuch as low temperature processing can be very cumbersome, special equipment is needed and moisture condensation during the process represents a potential problem.
It would be desirable to be able to mix the peptide or protein drug into a molten polymer, which could be cast into a defined shape and size. Unfortunately, most proteins denature at a temperature far below the melting point of polymers.
It is also desirable that the peptide or protein drug be stable under the conditions in which it is released from the polymeric matrix within the body. Most bioerodable polymers are depolymerized within the body by the hydrolysis of ester bonds. This hydrolysis can result in local regions of high acidity. Since many peptide or protein drugs are unstable in acidic conditions, this can result in deactivation of the drug before it is released. One such protein drug, which is unstable under acidic conditions, is basic fibroblast growth factor (bFGF). This protein, which has been isolated in forms varying in length, e.g. 146, 154 and 157 amino acid forms, is a potent angiogenic agent as well as a stimulator of cell proliferation and migration during wound healing. The DNA sequence encoding human bFGF and its deduced amino acid sequence are disclosed in U.S. Pat. No. 5,514,566. Because of its angiogenic properties, it is useful in promoting the local growth of new capillary vascular beds in order to bypass blockages in arteries of individuals having atherosclerotic conditions such as coronary artery disease and peripheral vascular disease. This protein is also chemotactic for fibroblasts, which are the chief cells involved in releasing a matrix required for wound healing, including collagen which determines the tensile strength of the healed wounds. In order to deliver bFGF effectively to a desired site and avoid any potential side effects associated with systemic delivery of bFGF in treating such conditions, it would be desirable to provide a controlled release device for implantation at or near the site at which the angiogenic or wound healing activity is required.